From Gold Thongs to Opioid Receptors: The Placebo Effect

placebo


Great Expectations

Rumor has it that when his batting average was precipitously low, Yankees first baseman Jason Giambi would slip on a gold thong before the game for some extra luck at the plate.  He swore that it always worked, and he was even generous enough to share it with his teammates on occasion.

There are countless other (perhaps not so colorful) examples of athletes who swear by borderline absurd rituals to bring them luck or break them out of a slump.  While superstitions and science are often irreconcilable, in this case there is indeed an underpinning of scientific truth to the thong effect.  Studies have shown that expecting to do well in a certain situation can boost performance.  For instance, participants in a memory experiment who brought their personal good luck charms to the lab performed better than their charm-deprived counterparts [1]. So when Giambi donned his gilded lingerie, he did tend to get more hits, likely not because of the scant undergarment itself but simply because he expected to do so.

The fact that confidence in one’s own abilities improves athletic or cognitive performance probably does not come as much of a shock.  But what about the fact that sugar water or saline can ameliorate a sick patient’s symptoms if he believes he is receiving an actual medication?  This pill is a bit more difficult to swallow, even though the concept is similar: when the brain expects something to happen, the brain can sometimes actually make that thing happen (to a certain degree).  In medicine, this is the “placebo effect”–when an inactive substance or sham procedure improves health simply because the patient expects it to do so.

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Have a Little Faith, There’s Magic in the… Sugar Water?

Today, placebos are used in clinical trials (you will often hear of “placebo-controlled trials”): a drug will not be approved by the FDA unless it works significantly better in treating patients than a placebo does. In the 19th century, however, placebos–bread pills, sugar pills, and water injections, to name a few–were commonly prescribed and administered by doctors [2] (can you imagine the lawsuits this would incur today??).  At that point in history, the purpose of the placebo was simply to decrease a patient’s anxiety. Eventually, however, physicians and others started to realize that these poppycock treatments played a part in physically curing patients. (For an intriguing story about a shaman who cured people by coughing up bloody feathers, check out this awesome radiolab podcast on placebos).

The idea of the placebo effect gained its first bit of respectable traction in 1955 when anesthesiologist Henry Beecher published a meta-analysis of a bunch of placebo-controlled trials with a shocking conclusion: in 35.2% of cases, the placebo had a significant therapeutic effect [3].  Beecher argued that there are two separate phases to suffering, the original sensation and then the brain’s processing of that sensation, and he proposed that placebos “provide an indispensable tool for the study of the reaction or processing component of suffering” [3].  In other words, he was the first to begin to look at placebos not from the point of view of a clinician testing a drug, but rather from the perspective of a neuroscientist interested in how expectation, anxiety, and the social context of treatment can affect the patient’s perception of symptoms.

The years since 1955 have produced countless interesting studies on placebos.  Inert substances administered as “drugs” have shown therapeutic efficacy in pain, itch, depression, and even Parkinson’s Disease, to name just a few. There is now a complementary body of literature on the “nocebo effect” in which patients anxious about side effects develop adverse reactions to an inactive substance.  There is even a study suggesting that the perceived cost of a drug can play a role–an “expensive” placebo was in some cases more effective than a “cheap” placebo [4]. And, amusingly, non-alcoholic drinks believed to be boozy have been shown to increase sexual arousal [5], aggressiveness [6], and memory distortion [7].  (So if you want to do your own experiment on placebos, you might consider throwing an O’Douls keg party.)

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But how does this happen??!  The underlying mechanisms still aren’t entirely clear to scientists, but we have uncovered a few helpful tidbits.

Curing the curiosity

 

synapse-thumb-250x282-94568Before you can understand how placebos work, it’s important to understand how active drugs work.  Brain cells such as the two pictured on the left are constantly sending signals to one another, and these signals control everything we do and think.  One cell releases certain types of molecules which bind to receptors on the receiving cell, causing some change in that cell and passing the signal forward.  Drugs (caffeine, cocaine, Zoloft, you name it!) usually work by one of three mechanisms: 1) the drug sits in the receptor to block the natural molecules’ access, thereby decreasing the signal or 2) the drug mimics the natural molecules and increases whatever signal is sent forward or 3) the drug increases the amount of time that the natural molecules stay in the synapse, also increasing the signal.

In 1999, a group in Italy made an important discovery about the molecules involved in the effect of placebo painkillers [8].  They injected capsaicin (the substance that makes red peppers painfully spicy!) under the skin on each participant’s right and left hand and right and left foot. Then, they spread some supposedly powerful pain-eradicating cream (which had no actual painkilling power whatsoever…shh!) on just one or of the four injection sites.  Patients reported a lessening of pain in the cream-covered location(s) but not in any of the other injection areas.  Another group of participants underwent the same ordeal, except they were pretreated with naloxone, a substance that blocks opioid receptors (among the natural molecules that bind to these receptors are endorphins).  It turns out that naloxone completely wiped out the placebo effect of the cream!  This means that these opioid receptors and their natural activators are likely involved in the placebo response to pain–brain cells might release more endorphins or other natural opioids when the person is expecting pain relief.  A few studies done in the years since have supported this finding.

More recently, advances in brain imaging have allowed researchers to look at which areas of the brain are active when patients receive placebos.  In 2004, a study was published detailing some specific brain regions involved in placebo effect [9].  Again, this study deals with placebo painkillers.  If placebos reduce the experience of pain, you would expect them to decrease brain activity in regions that control our response to pain (these include the somatosensory cortex, thalamus, insula, and anterior cingulate cortex).  Also, if placebos work because they mess with patients’ expectations, they must first cause brain activity in areas associated with internal representations of expectations (such as the dorsolateral prefrontal cortex and the oribitofrontal cortex), which in turn can affect activity in the pain-responsive areas.  The imaging results supported both of these conjectures.  Not only this, but in addition to activity in expectation-related areas before placebo application, the researchers saw increased activity in a region (called the periacqueductal grey) that contains a high concentration of those opioid receptors implicated by the Italian group!

 

Don’t Stop Believing

 

It’s not something we often think about, but every single aspect of our being–from the beating of our heart, to the moving of our limbs, to the storage of our most precious memories–is single-handedly controlled by the brain with its networks of billions of nerve cells.  Every perception we have of the outside world–from the recognizable voice of a friend, to the pinks and oranges of a sunset, to the glorious smell of pizza–is created by our brains as they process sound waves, light information, and little drifting pizza particles.  All things considered, maybe it’s not so preposterous that our perceptions of pain or other ills can change if our brain expects them to.

In the end, the message of placebos is a simple one: think positive, have confidence in modern medicine as well as in your natural immune system, and it’s ok to wear a gold thong once in a while if it helps you believe in yourself.

 

References

 

  1. Damisch L, Stoberock B, Mussweiler T. Keep your fingers crossed!: how superstition improves performance. Psychol Sci. 2010 Jul;21(7):1014-20.
  1. De Craen AJ, Kaptchuk TJ, Tijssen JG, Kleijnen J. Placebos and placebo effects in medicine: historical overview. Journal of the Royal Society of Medicine 1999;92(10):511-515.
  1. Beecher, HK. The Powerful Placebo. JAMA. 1955;159(17):1602-1606
  2. Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C, Allendorfer
    JB, Lang AE, Fleck DE, Linke MJ, Szaflarski JP. Placebo effect of medication cost
    in Parkinson disease: A randomized double-blind study. Neurology. 2015 Jan 28.
  3. Wilson G.T., Lawson D.M. Effects of alcohol on sexual arousal in male alcoholics. Journal of Abnormal Psychology, 1976 Dec;87:609–616
  4. Lang AR, Goeckner DJ, Adesso VJ, Marlatt, GA.  Effects of alcohol on aggression in male social drinkers. Journal of Abnormal Psychology, Vol 84(5), Oct 1975, 508-518.
  1.  Assefi SL, Garry M. Absolut memory distortions: alcohol placebos influence the
    misinformation effect. Psychol Sci. 2003 Jan;14(1):77-80.
  1. Benedetti F, Arduino C, Amanzio M. Somatotopic activation of opioid systems by
    target-directed expectations of analgesia
    . J Neurosci. 1999 May 1;19(9):3639-48.
  2. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM,
    Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and
    experience of pain. Science. 2004 Feb 20;303(5661):1162-7

Images

  1. http://www.biocomiche.it/2015/01/believe-to-be-cured-common-cold-rhinovirus-placebo-effect.html
  2. http://www.theage.com.au/articles/2004/05/05/1083635211039.html?from=moreStories
  3. http://www.funscrape.com/Cheez-Tag/Overconfident-Alcoholic
  4. http://www.qstorm.org/yang-lab-research-update/
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